EP1751102A1 - Process for producing a dipeptidyl peptidase iv inhibitor - Google Patents
Process for producing a dipeptidyl peptidase iv inhibitorInfo
- Publication number
- EP1751102A1 EP1751102A1 EP05754074A EP05754074A EP1751102A1 EP 1751102 A1 EP1751102 A1 EP 1751102A1 EP 05754074 A EP05754074 A EP 05754074A EP 05754074 A EP05754074 A EP 05754074A EP 1751102 A1 EP1751102 A1 EP 1751102A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- amide
- compound
- reaction mixture
- phosphorus oxychloride
- free base
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/52—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring condensed with a ring other than six-membered
Abstract
A process is provided for preparing the dipeptidyl peptidase of the structure (I) (also referred to as saxaglipitin) by direct dehydration, in one pot, of the amide II (II) by reacting amide II with phosphorus oxychloride in an organic solvent such as dichloromethane, quenching the reaction mixture with water to form the hydrochloric acid salt of I, and treating the hydrochloric acid salt with base to form the free base of I.
Description
PROCESS FOR PRODUCING A DIPEPTIDYL PEPTIDASE IV INHIBITOR
FIELD OF THE INVENTION This application claims a benefit of priority from U.S. Provisional Application No. 60/574,177, filed May 25, 2004, the entire disclosure of which is herein incorporated by reference. The present invention relates to a process for preparing (lS,3S,5S)-2-[(2S)-2- amino-2-(3-hydroxytricyclo[3.3.1.13'7] dec- 1 -yl)- 1 -oxoethyl] -2- azabicyclo[3.1.0]hexane-3-carbonitrile which is an inhibitor of dipeptidyl peptidase (DPP) IV and thus is useful in the treatment of diabetes and complications thereof, hyperglycemia, Syndrome X, hyperinsulinemia, obesity, and atherosclerosis and related diseases, as well as immunomodulatory diseases and chronic inflammatory bowel disease. BACKGROUND OF THE INVENTION Dipeptidyl peptidase IV is a membrane bound non-classical serine aminopeptidase which is located in a variety of tissues including, but not limited to, intestine, liver, lung, and kidney. This enzyme is also located on circulating T- lymphocytes wherein it is referred to as CD-26. Dipeptidyl peptidase IV is responsible for the metabolic cleavage of the endogenous peptides GLP- 1(7-36) and glucagons in vivo and has demonstrated proteolytic activity against other peptides such as GHRH, NPY, GLP-2 and VJP in vitro. GLP- 1(7-36) is a 29 amino acid peptide derived from post-translational processing of proglucagon in the small intestine. This peptide has multiple actions in vivo. For example, GLP- 1(7-36) stimulates insulin secretion and inhibits glucagon secretion. This peptide promotes satiety and slows gastric emptying. Exogenous administration of GLP- 1(7-36) via continuous infusion has been shown to be efficacious in diabetic patients. However, the exogenous peptide is degraded too rapidly for continual therapeutic use. Inhibitors of dipeptidyl peptidase IV have been developed to potentiate endogenous levels of GLP-l(7-36). U.S. Patent No. 6,395,767 to Hamann et al. discloses cyclopropyl-fused pyrrolidine-based inhibitors of dipeptidyl peptidase IV.
Methods for chemically synthesizing these inhibitors are disclosed in U.S. Patent No. 6,395,767 as well as in the literature. For example, see Sagnard et al. Tet-Lett. 1995 36:3148-3152; Tverezovsky et al. Tetrahedron 1997 53:14773-14792; and Hanessian et al. Bioorg. Med. Chem. Lett. 1998 8:2123-2128. A preferred inhibitor disclosed in U.S. Patent No. 6,395,767 is (lS,3S,5S)-2-[(2S)-2-amino-2-(3- hydroxytricyclo[3.3.1.13,7]dec-l-yl)-l-oxoethyl]-2-azabicyclo[3.1.0]hexane-3- carbonitrile, as depicted in Formulae M (HC1 salt) and M' (free base),
M" = monohydrate
and the corresponding monohydrate of (lS,3S,5S)-2-[(2S)-2-arnino-2-(3-hydroxy- tricyclo [3.3.1.13'7] dec- 1 -yl)- 1 -oxoethyl]-2-azabicyclo- [3.1.0] hexane-3 -carbonitrile (M") (all of which are collectively referred to as saxaglipitin). Methods adapted for preparing intermediates used in the production of this dipeptidyl peptidase TV inhibitor are disclosed in EP 0 808 824 A2. Also see, Imashiro and Kuroda Tetrahedron Letters 2001 42:1313-1315, Reetz et al. Chem. Int. Ed. Engl. 1979 18:72, Reetz and Heimbach Chem. Ber. 1983 116:3702-3707, Reetz et al. Chem. Ber. 1983 116:3708-3724. U.S. Application Serial No. 10/716,012 filed November 18, 2003 (attorney file LA84 NP) discloses a method for preparing a DPP4 inhibitor compound 4 which requires a dehydration of compound 1 using pyridine-trifluoroacetic anhydride to give a mixture of products having trifluoroacetate group protection on hydroxy and amine
or both (Compounds 6 and 7) and undehydrated-O-trifluoroacetate compound 5 as minor component. The nitriles 6 and 7 of the combined mixture then undergoes a hydrolysis step to give compound 2. Compound 1 is also formed in this reaction from compound 5, leading to loss of yield. If compound 1 is present in higher amounts after hydrolysis it may be difficult to remove it during crystallization of compound 2. Compound 2 is then subjected to another chemical process to deprotect the N-Boc group to form compound 3. HC1 which on basification forms compound 4. The above is illustrated by the following reaction sequence:
(minor component) Hydrolysis K2C03 - MeθH-H2θ
3 HC1, 4 Free base
As can be seen from the above reaction scheme, the amide 1 is converted to the HC1 salt 3 employing a three-step process wherein (1) amide 1 is made to undergo dehydration to form the cyano compounds 6 and 7; (2) the cyano compounds 6 and 7 are hydrolyzed to the alcohol 2, which is deprotected to form the HC1 salt 3. Although the above three-step procedure for producing HC1 salt 3 from amide 1 is adequate, any improvement in such procedure which involves direct conversion of amide 1 to the HC1 salt 3 (without the hydrolysis step) would be a most welcome improvement.
BRIEF DESCRIPTION OF THE INVENTION In accordance with the present invention, a process is provided for preparing a compound of the structure I (also referred to as saxaglipitin)
from amide H
employing a direct dehydration of the amide which contains a tertiary alcohol group and N-Boc deprotection, in preferably in one pot, thereby eliminating two chemical steps, namely hydrolysis and deprotection, ordinarily employed in previous processes as discussed above. The process for preparing a compound of the structure I
in accordance with the present invention includes the steps of a) providing an amide of the structure JJ
b) reacting the amide JJ with phosphorus oxychloride in an organic solvent, preferably dichloromethane, to form cyano compound HI
c) without isolating cyano compound JH, admixing water with the cyano compound ϋJ to form the product of structure I in the form of the hydrochloride salt.
The process of the invention as defined above may further include the step of treating the acid salt of product I with base to form the corresponding free base. In a preferred embodiment, the process of the invention is carried out as a one- pot process where the cyano compound HI is not isolated. In a preferred embodiment of the invention, the reaction mixture containing the amide JJ and phosphorus oxychloride in dichloromethane as the organic solvent is cooled to below about 5 °C and treated with water to form the hydrochloride salt. The hydrochloride salt is treated with base such as an alkali metal hydroxide such as NaOH, LiOH or KOH, to a pH within the range from about 7.0 to about 14.0 to form the product I in the form of its free base. The phosphorus oxychloride will preferably be employed in a molar ratio to amide JJ within the range from about 1 : 1 to about 99: 1.
DETAILED DESCRIPTION OF THE INVENTION The process of the invention for forming the DPP4 inhibitor I is depicted by the following reaction scheme:
SCHEME 1
No work up IA HCI salt IB Free base
The above direct dehydration reaction is preferably carried out in one pot without employing a hydrolysis step. The process is carried out by reacting amide JJ with a dehydrating agent, preferably phosphorus oxychloride, in an organic solvent, preferably dichloromethane. The dehydration reaction is carried out employing a molar ratio of dehydrating agent : to amide JJ within the range from about 1 : 1 to about 99: 1, preferably from
about 2: 1 to about 4: 1. Where phosphorus oxychloride is employed as the dehydrating agent, it is preferred to employ at least 3 equivalents of phosphorus oxychloride for each equivalent of amide JJ. The reaction is preferably carried out at room temperature to form cyano compound HI. On quenching the reaction mixture with water, compound DJ is converted to the HCI salt (IA) of compound I. The resulting reaction mixture is basified for example, by addition of base such as an alkali metal hydroxide, preferably NaOH, to a pH within the range from about 7.0 to about 14.0, more preferably about 9, to form the free base IB. The free base IB is separated from the reaction mixture preferably by adding sodium chloride. The resulting organic layer containing the free base is concentrated to leave the free base IB. Dehydration agents which may be employed herein include but are not limited to POCl3, tosyl chloride, formic acid, diphosphorus tetraiodide, trimethylsilyl polyphosphate, dipyridyl sulfite, PC13, PC15, P2O5, p-nitrobenzene sulfonyl chloride, ethyl polyphosphate, sodium borohydride, or phase transfer reagents i.e. PhCH2NEt3Cl, PhCH2NEt3Br, preferably POCl3. Organic solvents which may be employed herein include but are not limited to dichloromethane, toluene, chloroform, THF, acetonitrile, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, acetone, methyl isobutyl ketone, methyl ethyl ketone, 1,2-dimethoxyethane, 2-methyltetrahydrofuran, 1,4-dioxane, MTBE, chlorobenzene, xylenes, heptane, hexanes, cyclohexane, DMF, dimethyl sulfoxide, N- methylpyrrolidinone, ethanol, isopropanol, n-propanol, n-butanol or t-butanol, preferably dichloromethane. The amide may be prepared by the following reaction scheme which is described in detail in U.S. application Serial No. 10/716,012, filed November 18, 2003, which is incorporated herein by reference.
SCHEME 2
Coupling reaction
As shown in Scheme 2, the fragment (<aS)-<a-amino-3-hydroxytricyclo [3.3.1.13'7]decane-l-acetic acid (Formula IV) (prepared as described in U.S. application Serial No. 10/716,012 filed November 18, 2003 (Attorney File No. LA0084 NP)) which is incorporated herein by reference) is first BOC protected to produce (<aS )-<a[ [( 1 , 1 -dimethylethoxy)carbonyl] amino] -3 -hydroxytricyclo [3.3.1. l3'7]decane-l -acetic acid (Formula V) by treating IV with BOC2O in the presence of base such as sodium hydroxide and separated via ethyl acetate (EtOAc) extraction to separate out free acid V. Alternatively, in place of ethyl acetate, isopropyl acetate/heptane may be employed to crystallize out free acid V. A solution of Formula V compound in an appropriate organic solvent such as tetrahydrofuran (THF) (cooled to a temperature within the range from about -10 to about 0°C) is treated with methanesulfonyl chloride (Mesyl CI), and Hunig base (diisopropylethylamine or DJPEA) to form the corresponding methanesulfonic acid salt of V. A coupling reaction is then used to couple (<aS)-<a[[(l,l- dimethylethoxy)carbonyl] amino] -3-hydroxytricyclo[3.3.1.13'7] decane- 1 -acetic acid
(Formula V) methanesulfonic acid activated ester to (lS,3S,5S)-2- azabicyclo[3.1.0]hexane-3-carboxamide (Formula VI) (prepared as described in U.S. application Serial No. 10/716,012 filed November 18, 2003) in the presence of 1- hydroxybenzotriazole (HOBT) or other known coupling agent to produce 3- (aminocarbonyl)-<aS)-<a-(3-hydroxytricyclo[3.3.1.13'7]dec-l-yl)-<b-oxo-(lS,3S,5S)- 2-azabicyclo[3.1.0]hexane-2-ethanecarbamic acid, 1,1-dimethylethyl ester (Formula JJ). Starting amino acid compound TV is prepared as described in U.S. application Serial No. 10/716,012 filed November 18, 2003.
SCHEME 3
Referring to Scheme 3, the free base monohydrate IC may be formed from the
BOC-protected intermediate IA as follows. Hydrochloride salt IA is treated with sodium hydroxide or other base to form the free base IB. Free base IB may then be treated with water to form the free base monohydrate IC. Dipeptidyl peptidase IV inhibition produced using the processes of the present invention are useful in the treatment of diabetes and complications thereof, hyperglycemia, Syndrome X, hyperinsulinemia, obesity, and atherosclerosis and related diseases as well as immunomodulatory diseases and chronic inflammatory bowel disease.
EXAMPLES The following Examples represent preferred embodiments of the invention.
EXAMPLE 1 3-Cyano-(<aS)-<a-(3-hydroxytricyclo[3.3.1.13'7]dec-l-yl)-<b-oxo-(lS,3S,5S)-2- azabicyclo[3.1.0]hexane-2-ethanecarbamic acid, 1,1-dimethylethyl ester (Formula II)
A. BOC Protection of (<aS)-<a-amino-3-hydroxytricyclo[3.3.1.13'7] decane-1- acetic acid (Formula IV) to form (<aS)-<a[[(l,l-dimethylethoxy)- carbonyl]amino]-3-hydroxytricyclo[3.3.1.13'7]decane-l-acetic cid, (V) (<aS)-<a-amino-3-hydroxytricyclo[3.3.1.13,7]decane-l-acetic acid (Formula rV) (prepared as described in U.S. application Serial No. 10/716,012, filed November 18, 2003) (469 grams, 2.08 moles) was dissolved in ice cold 1 N NaOH (5 liters, 5 moles, 2.4 equivalents) in a phase splitter equipped with a temperature probe and a pH probe. THF (2.5 liters) was added to the solution. Solid Boc2O was then added and the reaction mixture was stirred at ambient temperature for approximately 1 hour. EtOAc (4 liters) was then added with stirring and the resulting organic and aqueous layers were separated. The pH of the aqueous layer was adjusted to 7 with concentrated HCI. EtOAc (4 liters) was then added and additional HCI was added to lower the pH to approximately 1. The total volume of concentrated HCI added was 510 ml. The organic and aqueous layers were again separated and the aqueous layer was extracted with EtOAc (3 x 3 liters). The organic layers were then combined and washed with water (3 liters) and brine (3 liters). The washed organic layer was then dried with Na2SO and concentrated on a rotovap at room temperature until dryness. The yield was 542 grams of (<aS)-<a[[(l,l-dimethylethoxy)carbonyl]amino]-3- hydroxytricyclo[3.3.1.1 ' ] decane-1 -acetic acid (Formula V).
B. 3-Cyano-(<aS)-<a-(3-hydroxytricyclo[3.3.1.13'7]dec-l-yl)-<b-oxo- (lS,3S,5S)-2-azabicyclo[3.1.0]hexane-2-ethanecarbamic acid, 1,1- dimethylethyl ester (Formula II) A 2 L three-necked flask equipped with a thermometer, a mechanical stirrer and a gas inlet was charged with Part A (<aS)-<a[[(l,l- dimethylethoxy)carbonyl]amino]-3-hydroxytricyclo[3.3.1.13'7]decane-l-acetic acid (Formula V) (50 grams, 153.8 mmol). THF (200 ml) was added and stirred to produce a clear solution. The solution was cooled to -6°C in an acetone-dry ice-water bath. Methanesulfonyl chloride (Mes-Cl)(13.1 ml, 169 mmol, 1.1 equivalents) was then added as a single portion followed by diisopropylethylamine (94 ml, 539 mmol, 1.1 equivalents). The diisopropylethylamine was added slowly over a period of about 4 minutes to keep the internal temperature below 8°C. The reaction mixture was stirred at 0 °C until all acid was converted to mixed anhydride. (lS,3S,5S)-2- azabicyclo[3.1.0]hexane-3-carboxamide hydrochloride salt (32.5 grams, 200 mmol, 1.1 equivalents) and hydroxybenzotriazole (HOBT) (1.04 grams, 7.6 mmol, 0.05 equivalents) were then added in a single portion and the flask was removed from the cooling bath. The reaction mixture was stirred at room temperature for 2 hours and then left overnight at room temperature. The reaction mixture was worked up by adding ethyl acetate and IN aqueous HCI and brine. The organic layer was separated and washed with 20% aqueous KHCO3 two times and then concentrated to a residue which was dried at 25 °C overnight. The retention time of the residue by HPLC was similar to an authentic sample of the amide JJ.
EXAMPLE 2 Preparation of Free Base Compound IB by Direct Dehydration of Example 1 Amide in a Single Pot
Deprotection
No work up IA HCI salt IB Free base
Example 1 amide compound JJ (433 mg) was dissolved in dichloromethane (2 mL) and phosphorus oxychloride (306 mg, 0.183 mL, 2 equiv) was added to it at room temperature. The reaction mixture was stirred at room temperature for 2.5 h. HPLC of the reaction mixture suggested 3% of Example 1 amide compound JJ present in it. The reaction mixture was diluted with additional dichloromethane (2 mL) followed by the addition of phosphorus oxychloride (150 mg, 0.09 mL, 1 equiv). The reaction mixture was stirred at room temperature for an additional 1 h. HPLC showed the absence of Example 1 compound IJ in the reaction mixture. The reaction mixture was cooled to <5°C and was slowly quenched by a dropwise addition of water (-10 mL), followed by stirring for 1 h at room temperature until compound JH disappeared in the reaction mixture. The reaction mixture was cooled to <5 °C and carefully basified to pH 9 by the addition of 10 N NaOH. Sodium chloride (5 g) was added as solid and the organic layer was separated. The aqueous layer was re-extracted with dichloromethane (3x10 mL). The combined organic layers were concentrated under vacuum at 25 °C to leave a white foamy residue, which was dried at 25 °C under vacuum for 16 h to give free base compound IB, 220 mg, 95% pure, 70% yield from Example 1 compound U. MS: m/e 316 (M+l)+, 338 (M+Na)+, 356 (M+Na+H2O)+, 360 (M-H+2 Na)+, 436 (M+Na+H3PO4)+, 653 (2M+Na)+, 671 (2 M+Na+H2O)+. The retention time of this product by HPLC was similar to authentic sample of free base compound IB. 1H NMR and 13CMR were in accordance with the structure for the free base IB.
Claims
1. The process for preparing a compound of the structure
which comprises a) providing an amide of the structure IJ
b) reacting the amide JJ with phosphorus oxychloride in an organic solvent; and c) treating the reaction mixture with water to form the product I in the form of its hydrochloride salt.
2. The process as defined in Claim 1 wherein in step b) the amide JJ is reacted with phosphorus oxychloride in an organic solvent to form cyano compound m in step c) without isolating cyano compound JJL the cyano compound IJJ is treated with water to form the product I in the form of its hydrochloric acid salt.
3. The process as defined in Claim 2 further including the step of treating the hydrochloric acid salt of product I with base to form the corresponding free base.
4. The process as defined in Claim 3 wherein the acid salt is treated with an alkali metal base to a pH of at least about 7.0.
5. The process as defined in Claim 2 in the form of a one-pot process where the cyano compound DJ is not recovered.
6. The process as defined in Claim 1 wherein the reaction of amide JJ and phosphorus oxychloride is carried out in the presence of dichloromethane as the organic solvent.
7. The process as defined in Claim 1 wherein the reaction mixture is cooled to below about 5 °C and treated with water to form the hydrochloride salt.
8. The process as defined in Claim 1 wherein the reaction of amide JJ with phosphorus oxychloride is carried out in one pot in dichloromethane.
9. The process as defined in Claim 7 wherein the reaction of amide IJ with phosphorus oxychloride is carried out at room temperature to form an intermediate compound of the structure
which without isolating is treated with water to form the compound I in the form of its free base.
10. The process as defined in Claim 3 wherein the reaction mixture containing the hydrochloride salt is cooled to below about 5 °C and treated with base to form the free base.
11. The process as defined in Claim 10 wherein the base is an alkali metal hydroxide and the reaction mixture is basified to a pH from about 7.0 to about 14.0.
12. The process as defined in Claim 1 wherein the phosphorus oxychloride is employed in a molar ratio to amide JJ within the range from about 1:1 to about 99:1.
13. The process as defined in Claim 1 carried out in one pot employing about 3 equivalents of phosphorus oxychloride to about one equivalent of amide JJ.
14. The process as defined in Claim 13 carried out in the presence of dichloromethane.
15. The process as defined in Claim 14 wherein the reaction mixture is quenched with water to form the product I in the form of its hydrochloric acid salt.
16. The process as defined in Claim 15 wherein the reaction mixture is basified with NaOH to about pH 9 and the product I is recovered in the form of its free base.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US57417704P | 2004-05-25 | 2004-05-25 | |
| PCT/US2005/018205 WO2005115982A1 (en) | 2004-05-25 | 2005-05-24 | Process for producing a dipeptidyl peptidase iv inhibitor |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| EP1751102A1 true EP1751102A1 (en) | 2007-02-14 |
Family
ID=35450809
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP05754074A Withdrawn EP1751102A1 (en) | 2004-05-25 | 2005-05-24 | Process for producing a dipeptidyl peptidase iv inhibitor |
Country Status (3)
| Country | Link |
|---|---|
| US (1) | US7214702B2 (en) |
| EP (1) | EP1751102A1 (en) |
| WO (1) | WO2005115982A1 (en) |
Families Citing this family (33)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7420079B2 (en) * | 2002-12-09 | 2008-09-02 | Bristol-Myers Squibb Company | Methods and compounds for producing dipeptidyl peptidase IV inhibitors and intermediates thereof |
| US7741082B2 (en) | 2004-04-14 | 2010-06-22 | Bristol-Myers Squibb Company | Process for preparing dipeptidyl peptidase IV inhibitors and intermediates therefor |
| PE20071221A1 (en) | 2006-04-11 | 2007-12-14 | Arena Pharm Inc | GPR119 RECEPTOR AGONISTS IN METHODS TO INCREASE BONE MASS AND TO TREAT OSTEOPOROSIS AND OTHER CONDITIONS CHARACTERIZED BY LOW BONE MASS, AND COMBINED THERAPY RELATED TO THESE AGONISTS |
| PE20090696A1 (en) | 2007-04-20 | 2009-06-20 | Bristol Myers Squibb Co | CRYSTALLINE FORMS OF SAXAGLIPTIN AND PROCESSES FOR PREPARING THEM |
| CL2008002427A1 (en) | 2007-08-16 | 2009-09-11 | Boehringer Ingelheim Int | Pharmaceutical composition comprising 1-chloro-4- (bd-glucopyranos-1-yl) -2- [4 - ((s) -tetrahydrofuran-3-yloxy) benzyl] -benzene combined with 1 - [(4-methylquinazolin- 2-yl) methyl] -3-methyl-7- (2-butyn-1-yl) -8- (3- (r) -aminopiperidin-1-yl) xanthine; and its use to treat type 2 diabetes mellitus. |
| EP2146210A1 (en) | 2008-04-07 | 2010-01-20 | Arena Pharmaceuticals, Inc. | Methods of using A G protein-coupled receptor to identify peptide YY (PYY) secretagogues and compounds useful in the treatment of conditions modulated by PYY |
| UY32030A (en) | 2008-08-06 | 2010-03-26 | Boehringer Ingelheim Int | "TREATMENT FOR DIABETES IN INAPPROPRIATE PATIENTS FOR THERAPY WITH METFORMIN" |
| WO2010018217A2 (en) | 2008-08-15 | 2010-02-18 | Boehringer Ingelheim International Gmbh | Organic compounds for wound healing |
| AR074990A1 (en) | 2009-01-07 | 2011-03-02 | Boehringer Ingelheim Int | TREATMENT OF DIABETES IN PATIENTS WITH AN INAPPROPRIATE GLUCEMIC CONTROL THROUGH METFORMIN THERAPY |
| TWI466672B (en) | 2009-01-29 | 2015-01-01 | Boehringer Ingelheim Int | Treatment for diabetes in paediatric patients |
| EA029759B1 (en) | 2009-02-13 | 2018-05-31 | Бёрингер Ингельхайм Интернациональ Гмбх | Antidiabetic medications comprising dpp-4 inhibitor (linagliptin) optionally in combination with other antidiabetic agents |
| AU2010212867B2 (en) | 2009-02-13 | 2013-05-16 | Boehringer Ingelheim International Gmbh | Pharmaceutical composition comprising a SGLT2 inhibitor, a DPP-IV inhibitor and optionally a further antidiabetic agent and uses thereof |
| MX2011009852A (en) * | 2009-03-27 | 2011-09-29 | Bristol Myers Squibb Co | Methods for preventing major adverse cardiovascular events with dpp-iv inhibitors. |
| EP3646859A1 (en) | 2009-11-27 | 2020-05-06 | Boehringer Ingelheim International GmbH | Treatment of genotyped diabetic patients with dpp-iv inhibitors such as linagliptin |
| US20130109703A1 (en) | 2010-03-18 | 2013-05-02 | Boehringer Ingelheim International Gmbh | Combination of a GPR119 Agonist and the DPP-IV Inhibitor Linagliptin for Use in the Treatment of Diabetes and Related Conditions |
| AU2011249722B2 (en) | 2010-05-05 | 2015-09-17 | Boehringer Ingelheim International Gmbh | Combination therapy |
| WO2011140328A1 (en) | 2010-05-05 | 2011-11-10 | Teva Pharmaceutical Industries Ltd. | Saxagliptin intermediates, saxagliptin polymorphs, and processes for preparation thereof |
| BR112012032579B1 (en) | 2010-06-24 | 2021-05-11 | Boehringer Ingelheim International Gmbh | use of linagliptin and pharmaceutical composition comprising linagliptin and long-acting basal insulin |
| EP2608788A1 (en) | 2010-10-04 | 2013-07-03 | Assia Chemical Industries Ltd. | Polymorphs of saxagliptin hydrochloride and processes for preparing them |
| EA201490556A1 (en) | 2011-09-07 | 2014-08-29 | Сановел Илач Санайи Ве Тиджарет Аноним Ширкети | COMPOSITIONS OF DPP-4 INHIBITOR |
| PL2578208T3 (en) | 2011-10-06 | 2014-10-31 | Sanovel Ilac Sanayi Ve Ticaret As | DPP-IV inhibitor solid dosage formulations |
| US8664443B2 (en) | 2012-05-23 | 2014-03-04 | Divi's Laboratories Ltd. | Process for the preparation of (1S, 3S, 5S)-2-[2(S)-2-amino-2-(3-hydroxy-1-adamantan-1-yl) acetyl]-2-azabicyclo [3.1.0] hexane-3-carbonitrile |
| CA2885957C (en) | 2012-05-24 | 2019-10-22 | Apotex Pharmachem India Pvt. Ltd | Salts of saxagliptin with organic acids |
| WO2013174767A1 (en) | 2012-05-24 | 2013-11-28 | Boehringer Ingelheim International Gmbh | A xanthine derivative as dpp -4 inhibitor for use in modifying food intake and regulating food preference |
| WO2013179297A1 (en) * | 2012-05-30 | 2013-12-05 | Rao Davuluri Ramamohan | Process for preparation of (1s, 3s, 5s)-2-[(2s)-2-amino-2-(3-hydroxy-1-adamantyl) acetyl]-2-azabicyclo [3.1.0] hexane-3-carbonitrile |
| AU2013285078A1 (en) | 2012-07-02 | 2015-01-29 | Sun Pharmaceutical Industries Limited | Saxagliptin salts |
| WO2014108830A1 (en) | 2013-01-10 | 2014-07-17 | Wockhardt Limited | A process for preparing pharmaceutically acceptable salt of saxagliptin |
| CN103965065B (en) * | 2013-02-01 | 2016-02-17 | 上海现代制药股份有限公司 | Onglyza intermediate, its salt, Its Preparation Method And Use |
| CN103265473A (en) * | 2013-06-04 | 2013-08-28 | 上海同昌生物医药科技有限公司 | Method for producing saxagliptin |
| US9416105B2 (en) | 2013-08-28 | 2016-08-16 | Amneal Pharmaceuticals Llc | Process for preparation of saxagliptin and its hydrochloride salt |
| CN104649953A (en) * | 2013-11-25 | 2015-05-27 | 天津市汉康医药生物技术有限公司 | Saxagliptin sesquihydrate compound |
| CZ2014177A3 (en) * | 2014-03-24 | 2015-10-07 | Zentiva, K.S. | Process for preparing saxagliptin |
| WO2019241574A1 (en) | 2018-06-14 | 2019-12-19 | Astrazeneca Uk Limited | Methods for lowering blood sugar with a dipeptidyl peptidase-4 inhibitor pharmaceutical composition |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IL120873A0 (en) | 1996-05-24 | 1997-09-30 | Tanabe Seiyaku Co | Process for preparing optically active 2-halogen-3-hydroxypropionic acid ester |
| US6068991A (en) | 1997-12-16 | 2000-05-30 | Bristol-Myers Squibb Company | High expression Escherichia coli expression vector |
| EP1097236A4 (en) | 1998-07-15 | 2006-10-04 | Bristol Myers Squibb Co | Stereoselective reductive amination of ketones |
| US6395767B2 (en) | 2000-03-10 | 2002-05-28 | Bristol-Myers Squibb Company | Cyclopropyl-fused pyrrolidine-based inhibitors of dipeptidyl peptidase IV and method |
| US7420079B2 (en) | 2002-12-09 | 2008-09-02 | Bristol-Myers Squibb Company | Methods and compounds for producing dipeptidyl peptidase IV inhibitors and intermediates thereof |
-
2005
- 2005-05-23 US US11/135,217 patent/US7214702B2/en active Active
- 2005-05-24 WO PCT/US2005/018205 patent/WO2005115982A1/en not_active Application Discontinuation
- 2005-05-24 EP EP05754074A patent/EP1751102A1/en not_active Withdrawn
Non-Patent Citations (1)
| Title |
|---|
| See references of WO2005115982A1 * |
Also Published As
| Publication number | Publication date |
|---|---|
| US7214702B2 (en) | 2007-05-08 |
| WO2005115982A1 (en) | 2005-12-08 |
| US20050267191A1 (en) | 2005-12-01 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US7214702B2 (en) | Process for producing a dipeptidyl peptidase IV inhibitor | |
| US7420063B2 (en) | Process for preparing a dipeptidyl peptidase IV inhibitor and intermediates employed therein | |
| US11479535B2 (en) | Methods for the synthesis of activated ethylfumarates and their use as intermediates | |
| US7754757B2 (en) | Bicycloester derivative | |
| US8461352B2 (en) | Process for preparing azabicyclic compounds | |
| US7514571B2 (en) | Bicyclo derivative | |
| TW200808770A (en) | Novel processes for the preparation of DPP IV inhibitors | |
| JP2006516121A5 (en) | ||
| EP2368874A1 (en) | Racemisation of (R)-N-Boc-3-hydroxyadamant-1-yl glycine | |
| US20060106086A1 (en) | Preparation of tegaserod and tegaserod maleate | |
| US5420283A (en) | Resolution of (R)-2-benzylsuccinic acid 4-[4-(N-t-butoxycarbonylmethylamino)-piperidine] amide | |
| US9346853B2 (en) | Synthesis of telaprevir and boceprevir, or pharmaceutically acceptable salts or solvates as well as intermediate products thereof including β-amino acids prepared via Mukaiyama aldol addition | |
| KR20230022874A (en) | Synthesis of (2S,5R)-5-(2-chlorophenyl)-1-(2'-methoxy-[1,1'-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid | |
| US8748457B2 (en) | 2-amino-2- [8-(dimethyl carbamoyl)- 8-aza- bicyclo [3.2.1] oct-3-yl]-exo- ethanoyl derivatives as potent DPP-IV inhibitors | |
| KR101214435B1 (en) | Process for the preparation of nateglinide | |
| US9416105B2 (en) | Process for preparation of saxagliptin and its hydrochloride salt | |
| CN110357787A (en) | Yi Shazuo meter synthesising process research | |
| MXPA06008909A (en) | Bicycloester derivative |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
| 17P | Request for examination filed |
Effective date: 20061127 |
|
| AK | Designated contracting states |
Kind code of ref document: A1 Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LI LT LU MC NL PL PT RO SE SI SK TR |
|
| AX | Request for extension of the european patent |
Extension state: HR LV MK YU |
|
| RAX | Requested extension states of the european patent have changed |
Extension state: YU Payment date: 20061127 Extension state: MK Payment date: 20061127 Extension state: LV Payment date: 20061127 Extension state: HR Payment date: 20061127 |
|
| STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE APPLICATION HAS BEEN WITHDRAWN |
|
| 18W | Application withdrawn |
Effective date: 20090227 |